Case report: A first case of desmin-related myofibrillar myopathy due to inheritance from a confirmed mosaic asymptomatic carrier

Jelle Vlaeminck^1*Sophie Uyttebroeck¹Elke De Schutter¹Ann Cordenier²Shauni Wellekens³Erwin Ströker⁴Kelly De Rooms¹Christine Helsen¹Frederik Jan Hes¹Philippe Giron^1*

• ¹Centre for Medical Genetics, Research group Genetics, Reproduction and Development (GRAD), Clinical Sciences, Universitair Ziekenhuis Brussel (UZ Brussel)-Vrije Universiteit Brussel (VUB), Jette, Belgium
• ²Department of Neurology, Center for Neurosciences, Universitair Ziekenhuis Brussel (UZ Brussel)-Vrije Universiteit Brussel (VUB), Jette, Belgium
• ³Department of Respiratory Medicine, Universitair Ziekenhuis Brussel (UZ Brussel)-Vrije Universiteit Brussel (VUB), Jette, Belgium
• ⁴Heart Rhythm Management Centre, Universitair Ziekenhuis Brussel (UZ Brussel)-Vrije Universiteit Brussel (VUB), Jette, Belgium

Desmin-related myofibrillar myopathy is a hereditary disorder caused by pathogenic variants in the DES gene (MIM*125660), altering desmin, a muscle-specific intermediate filament which is crucial for sarcomere integrity. This condition presents with skeletal myopathy, cardiomyopathy, and conduction abnormalities. Genetic counselling for index patients and their family members is complicated by variable expressivity, incomplete penetrance, and de novo occurrence. Mosaicism in asymptomatic parents can obscure inheritance patterns, particularly when low-grade mosaic variants in blood may be missed. In case of DES, mosaic carriership has not been described before.We describe a case of a 24-year-old female diagnosed with desmin-related myopathy due to a heterozygous pathogenic NM_001927.4(DES):c.1216C>T, p.Arg406Trp variant. Cascade testing using targeted Sanger sequencing of her asymptomatic parents suggested the mother is a mosaic carrier of the pathogenic variant, which was confirmed though next-generation sequencing. The proband's siblings did not carry the DES c.1216C>T variant.We report the first documented case of mosaic carriership of a pathogenic DES variant in an asymptomatic individual and subsequent inheritance by the offspring, leading to desmin-related myopathy. This report highlights the importance of cascade testing in hereditary disorders with a focus on mosaicism, even when the index's biological parents are asymptomatic, and de novo emergence is suspected.